The present invention relates to non-steroidal compounds that demonstrate high-binding affinity for the estrogen receptor, while being devoid of any agonistic effects on reproductive tissues and to non-steroidal compounds that have a high binding affinity for the estrogen receptor while also having some agonistic activity specific to the skeletal and cardiovascular systems. More particularly, the present invention relates to novel non-steroidal ligands for the estrogen receptor as well as methods of making the same and their applications in treating a variety of disease states.
Interfering with the activity of endogenously produced estrogens can modulate the course of many estrogen-dependent diseases. One approach has been to prevent estrogen biosynthesis using inhibitors of aromatase enzymes, which are responsible for the conversion of androgens to estrogens. Alternatively, estrogen activity may be interrupted at the receptor level using estrogen antagonists.
The involvement of estrogens in the development and progression of breast cancer has been known for over 100 years. In normal breast tissue, only 6% of the mammary epithelial cells express estrogen receptors (McDonnell et al., Ann. N. Y. Acad. Sci. 1996; 121-37), whereas over 60% of primary breast tumors are estrogen receptor positive and are dependent on estrogen for growth. However, it has been documented that other agents (e.g. growth factors) can activate estrogen receptors in the absence of estrogen (Pareczyk and Schneider, J. Cancer Res. Clin. Oncol. 1996; 122:383-96). As a result, blocking activity at the estrogen receptor is potentially a more effective therapeutic strategy than inhibition of estrogen biosynthesis.
Tamoxifen, a triphenylethene derivative, is the most widely used anti-estrogen for the treatment of breast cancer. It is predominantly used as a first-line therapy in metastatic breast cancer to prolong survival. Unfortunately, resistance to tamoxifen usually develops within 15 months of therapy initiation. Nevertheless, the clinical efficacy of tamoxifen as a hormonal therapy for many types of breast cancer has led to the search for more potent estrogen receptor antagonists.
Several new antiestrogens including toremifene, droloxifene, idoxifene, TAT-59 and raloxifene are currently being evaluated in the laboratory and in the clinic for the treatment of estrogen related disorders (Gradishar and Jordan, J. Clin. Oncol. 1997; 15(2):840-52). There has been considerable concern regarding the long-term use of tamoxifen due to an increase in incidences of endometrial cancer, deep venous thrombosis and pulmonary embolism for patients receiving the therapy (Rauschning and Pritchard, Breast Cancer Res. Treat 1994; 31:83-94). Other more common side effects include, hot flushes, vaginal bleeding and blurred vision (Nicholson R I, Bailliere and Tindall, 1987:60-87). Despite these side effects, results from one clinical study have demonstrated the utility of tamoxifen in the prevention of breast cancer in women at high risk of developing the disease (Fisher et al, J. of the Nat""l Cancer Inst. 1998; Vol. 90; No. 18; 1371-1388). The FDA has approved tamoxifen for use as a prophylactic.
It has been suggested that the partially agonistic properties of some anti-estrogens are responsible for both their side-effect profile and the development of resistance to therapy (Nicholson et al., Ann. N. Y. Acad. Sci. 1996; 784:-325-35). Partial agonists are compounds for which the balance in the expression of antagonistic and agonistic activity depends on the dose administered, as well as on the species and target organ studied. More specifically, differences in agonistic/antagonistic responses depend on the presence of cell-specific proteins that can act as co-activators or transcription factors (Mitlak and Cohen, Horm. Res. 1997; 48:155-63). In vitro and in vivo experiments have suggested that the agonistic properties of some anti-estrogens may become dominant through the course of therapy. This has been demonstrated in clinical settings where 10-30% of tamoxifen-resistant patients showed improvement of their diseases after withdrawal from tamoxifen therapy (Parczyk and Schneider, J. Cancer Res. Clin. Oncol. 1996; 122:383-96).
xe2x80x9cPurexe2x80x9d anti-estrogens are compounds that have exclusively antagonistic properties and lead to the formation of inactive ligand-receptor complexes. In contrast to partial agonists that stimulate the expression of estrogen receptors, pure anti-estrogens cause a down-regulation of cellular receptor protein levels (Parczyk and Schneider, J. Cancer Res. Clin. Oncol. 1996; 122:383-96). Since the estrogen receptor is activated through estrogen-independent factors, the reduction in estrogen receptor levels obtained with pure anti-estrogens may offer clinical advantages over partial agonists and aromatase inhibitors. Clinical trials with pure anti-estrogens have shown efficacy against tamoxifen-resistant breast cancers where approximately two-thirds of tamoxifen-resistant patients responded to ICI 182780 (faslodex), and no significant adverse effects were observed (England and Jordan, Oncol. Res. 1997; 9:397-402).
Many studies performed to date have suggested that anti-estrogens with partial agonistic activity have positive effects on cardiovascular and skeletal systems. For example, tamoxifen lowers total and LDL cholesterol, lowers lipoprotein (A) and preserves bone mass in postmenopausal women undergoing breast cancer treatment (Mitlak and Cohen, Horm. Res. 1997; 48:155-63). Estrogens play an important role in the regulation and synthesis of lipids and therefore have a protective effect on the cardiovascular system. Following menopause, the risk of developing atherosclerosis and coronary disorders dramatically increases in women not undergoing hormone replacement therapy. In addition, estrogens are critically important in the maintenance of proper bone mass. As the circulating level of estrogen decreases, post-menopausal women experience an increase in the rate of bone turnover, resulting in net bone loss. Therefore, the positive effects of tamoxifen observed on skeletal and cardiovascular systems may be related to agonistic activity through the estrogen receptor present in those tissues (Mitlak and Cohen, Horm. Res. 1997; 48:155-63).
Other partial agonists currently in development have demonstrated anti-estrogenic effects on reproductive tissues with increased protective effects or estrogenic activity on the skeletal and cardiovascular systems. These compounds are known as Selective Estrogen Receptor Modulators (SERMs). Examples of these include droloxifene, which is being developed as an anti-osteoporotic agent, and raloxifene, which has been approved by the FDA for prevention of osteoporosis in post-menopausal women.
Although anti-cancer agents fall into specific classifications, it is not uncommon for agents to act by multiple modes of action. For example, tamoxifen has been shown to have anti-proliferative activity on cancer cells and endothelial cells by an estrogen independent mechanism. Taxol, an anti-mitotic agent acting on microtubules has also demonstrated anti-angiogenic properties, possibly by inducing apoptosis through Bcl-2 phosphorylation. These are but a few examples and the fact that some anti-estrogens have demonstrated anti-angiogenic properties is of particular interest to many in this field of research. Such a possibility is not precluded in the present invention.
There thus remains a need to develop a series of non-steroidal compounds that demonstrate high-binding affinity for the estrogen receptor, while being devoid of any agonistic effects on reproductive tissues. Alternatively, non-steroidal compounds that have a high binding affinity for the estrogen receptor and have some agonistic activity specific to the skeletal and cardiovascular systems are also desirable. Therefore, either pure anti-estrogens or partial anti-estrogens with high binding affinity, low toxicity and prolonged efficacy would be of great benefit.
The present invention seeks to meet these and other needs.
The present description refers to a number of documents, the content of which is herein incorporated by reference in their entirety.
It has now been discovered that certain novel estrogen binding ligands that have been shown to be anti-proliferative against human estrogen-dependent cancer cells and having a high binding affinity for the estrogen receptor can be constructed as set forth herein.
In one embodiment, the present invention relates to a series of non-steroidal compounds that demonstrate high-binding affinity for the estrogen receptor, while being devoid of any agonistic effects on reproductive tissues.
In another embodiment, the present invention also relates to either pure anti-estrogens or partial anti-estrogens with high binding affinity, low toxicity and prolonged efficacy.
In yet another embodiment, the present invention relates to non-steroidal anti-estrogens based on the tetra-cyclic derivatives described herein and as described in their synthetic pathways.
In addition, in another embodiment the present invention seeks to provide non-steroidal anti-estrogens having good affinity for estrogen receptors.
In accordance with another embodiment, the present invention seeks to provide a therapeutic anti-estrogen composition useful in the treatment of estrogen-related diseases. These diseases include, but are not limited to breast cancer, uterine cancer, ovarian cancer, osteoporosis, cardiovascular diseases, premenstrual syndrome, uterine fibroma, endometriosis, precocious puberty, vasomotor symptoms associated with menopause, atrophic vaginitis, CNS disorders (including Alzheimer""s), infertility, glaucoma and elevated serum cholesterol.
The above and other embodiments are accomplished by providing a pharmaceutical composition comprising a therapeutically effective amount of an anti-estrogen specified herein. As used herein, the terms R1, R2, R3, R4 and R5 refer to substituents whose location on the tetra-cyclic skeleton is illustrated as depicted in Formula 1 below: 
and wherein the A and D rings are always aromatic.
Certain preferred substituents include, but are not limited to the following:
Z is C (carbon) where the B-ring and C-ring are aromatic. Alternatively where Z is carbon, the B-ring may be unsaturated and the C-ring aromatic. In another embodiment where Z is carbon, the B-ring is aromatic and the C-ring is unsaturated. In all embodiments where Z is carbon the R1, R2, R3, R4, and R5 substituents are as described below. Z can also be either O (oxygen) or S (sulfur) in an alternate embodiment in which case the B-ring is not aromatic, but the C-ring may or may not be aromatic and R1 to R5 are as described below.
Certain preferred substituents for R1 include, but are not limited to 1-pyrrolidinyl or 1-piperidinyl, methyl-1-pyrrolidinyl, dimethyl-1-pyrrolidino, 4-morpholino, dimethylamino, diethylamino, diisopropylamino, or 1-hexamethyleneimino and n is an integer from 1 to 4. The nitrogen atom contained in the pyrrolidine and piperidine functional groups is expected to be predominantly protonated at physiological pH.
The preferred orientation of the bond linking the B and D rings is as shown below in Formula 2. The wedged line indicates the preferred configuration. 
It has been documented that a correctly positioned alkylaminoethoxy side chain may be required for anti-estrogenic activity (Levenson and Jordan, Cancer Res. 1998; 58:1872-75). Compounds containing such a side chain positioned in an orthogonal orientation as shown in Formula 1, relative to a tetracyclic steroid-like skeleton, have demonstrated full antagonistic activity on uterine and mammary tissues (Grese et al., J. Med. Chem. 1998; 41:1272-83). Furthermore, the incorporation of the nitrogen atom into a ring system such as in pyrrolidine or piperidine acts to prevent potential toxicity associated with N-dealkylation that has been shown for example to occur readily with the dimethylaminoethoxy side chain of tamoxifen (Gradishar and Jordan, J. Clin. Oncol. 1997; 15(2):840-52).
Certain preferred substituents for R2 include but are not limited to CH2CH2CH3, CH2C(CH3)2H, CH(OH)CH2CH3, CHxe2x95x90CHCH3, CHxe2x95x90CHCH(CH3)2, CH3Cxe2x95x90CH2, Cxe2x95x90OCH3, Cxe2x95x90OCH2CH3, Cxe2x95x90OCH(CH3)2, Cxe2x95x90OCHxe2x95x90CH2, Cxe2x95x90OCHxe2x95x90C(CH3)H, Cxe2x95x90OCHxe2x95x90C(CH3)2, C(CH3)xe2x95x90C(CH3)2 and CH(OH)CH3.
Certain preferred substituents for R3 and R4 include, but are not limited to hydrogen and hydrogen respectively, hydrogen and methyl respectively, methyl and hydrogen respectively or methyl and methyl respectively. It is believed that methylation at these sites will prevent the formation of potentially carcinogenic or mutagenic metabolites such as epoxides and will thus further reduce the potential toxicity of the structure.
Certain preferred substituents for R5 include, but are not limited to OH or OCxe2x95x90OCH3. The hydroxyl group at R5 is preferred for hydrogen bond formation with the estrogen receptor and will eliminate the dependence on in vivo hydroxylation for biological activity. It is believed that compounds containing an ester or a methoxy substituent at the R5 position would require metabolic activation for the functional group transformation to the hydroxyl form, which is required for high affinity interaction with the estrogen receptor.
In accordance with the present invention, there is therefore provided a compound of Formula 1 comprising A, B, C and D rings, or a pharmaceutically acceptable salt or ester thereof, 
wherein R1 represents a substituent selected from the group consisting of 1-pyrrolidinyl, 1-piperidinyl, methyl-1-pyrrolidinyl, dimethyl-1-pyrrolidino, 4-morpholino, dimethylamino, diisopropylamino and 1-hexamethyleneimino; wherein R2 represents a substituent selected from the group consisting of CH2CH2CH3, CH2C(CH3)2H, CH(OH)CH2CH3, CHxe2x95x90CHCH3, CHxe2x95x90CHCH(CH3)2, CH3Cxe2x95x90CH2, Cxe2x95x90OCH3, Cxe2x95x90OCH2CH3, Cxe2x95x90OCH(CH3)2, Cxe2x95x90OCHxe2x95x90CH2, Cxe2x95x90OCHxe2x95x90C(CH3)H, Cxe2x95x90OCHxe2x95x90C(CH3)2, C(CH3)xe2x95x90C(CH3)2 and CH(OH)CH3; wherein R3 and R4 can be a hydrogen atom or a methyl group; wherein R5 is a hydroxy group or an ester group represented by the formula (OCxe2x95x90OCH3); wherein xe2x80x9cnxe2x80x9d is an integer from 1 to 4; wherein xe2x80x9czxe2x80x9d is a carbon atom, an oxygen atom or a sulfur atom; wherein at least one of the mentioned B-ring or C-ring is aromatic when xe2x80x9czxe2x80x9d is a carbon atom and wherein the B-ring is not aromatic and the C-ring can be aromatic when xe2x80x9czxe2x80x9d is either oxygen or sulfur.
In accordance with the present invention, there is also provided a process for the preparation of a compound of Formula 1, wherein xe2x80x9czxe2x80x9d is an oxygen atom, involving the reaction of a molecule of Formula 1.8 comprising A, B, C and D rings; 
wherein R1 represents a substituent selected from the group consisting of 1-pyrrolidinyl, 1-piperidinyl, methyl-1-pyrrolidinyl, dimethyl-1-pyrrolidino, 4-morpholino, dimethylamino, diisopropylamino and 1-hexamethyleneimino; wherein R6 represents a substituent selected from the group consisting of CH3, CH2CH3, CH(CH3)2, CHxe2x95x90CH2, CHxe2x95x90CHCH3 and CHxe2x95x90C(CH3)2; wherein R3 and R4 can be a hydrogen atom or a methyl group; wherein xe2x80x9cnxe2x80x9d is an integer from 1 to 4; and wherein the B-ring is non-aromatic and the C-ring is aromatic; with either BBr3 or concentrated HBr followed by the recovery of the compound of FIG. 1 from the reaction mixture.
In accordance with the present invention, there is also provided a process for the preparation of a compound of Formula 1, wherein xe2x80x9czxe2x80x9d is a carbon atom and wherein the B and C-rings are aromatic, involving the reaction of a molecule of Formula 2-7 comprising A, B, C and D rings; 
wherein R6 represents a substituent selected from the group consisting of CH3, CH2CH3, CH(CH3)2, CHxe2x95x90CH2, CHxe2x95x90CHCH3 and CHxe2x95x90C(CH3)2; wherein R3 and R4 can be a hydrogen or a methyl group; and wherein the mentioned B-ring and C-ring are aromatic; with a reagent having the general formula Cl(CH2)nR1; wherein R1 represents a substituent selected from the group consisting of 1-pyrrolidinyl, 1-piperidinyl, methyl-1-pyrrolidinyl, dimethyl-1-pyrrolidino, 4-morpholino, dimethylamino, diisopropylamino and 1-hexamethyleneimino and wherein xe2x80x9cnxe2x80x9d is an integer from 1 to 4; followed by the recovery of the compound of FIG. 1 from the reaction mixture.
In accordance with the present invention, there is also provided a process for the preparation of a compound of Formula 1, wherein xe2x80x9czxe2x80x9d is a carbon atom, and wherein the B- and C-rings are aromatic, involving the reaction of a molecule of Formula 2-8 comprising A, B, C and D rings; 
wherein R1 represents a substituent selected from the group consisting of 1-pyrrolidinyl, 1-piperidinyl, methyl-1-pyrrolidinyl, dimethyl-1-pyrrolidino, 4-morpholino, dimethylamino, diisopropylamino and 1-hexamethyleneimino; wherein R6 represents a substituent selected from the group consisting of CH3, CH2CH3, CH(CH3)2, CHxe2x95x90CH2, CHxe2x95x90CHCH3 and CHxe2x95x90C(CH3)2; wherein R3 and R4 can be a hydrogen atom or a methyl group; wherein xe2x80x9cnxe2x80x9d is an integer from 1 to 4 and wherein the mentioned B-ring and C-ring are aromatic; with a reducing agent selected from the group consisting of H2/Pd-C and NaBH4 followed by the recovery of the compound of FIG. 1 from the reaction mixture.
In accordance with the present invention, there is also provided a process for the preparation of a compound of Formula 1, wherein xe2x80x9czxe2x80x9d is a carbon atom, involving the reaction of a molecule of Formula 2-8 comprising A, B, C and D rings; 
wherein R1 represents a substituent selected from the group consisting of 1-pyrrolidinyl, 1-piperidinyl, methyl-1-pyrrolidinyl, dimethyl-1-pyrrolidino, 4-morpholino, dimethylamino, diisopropylamino and 1-hexamethyleneimino; wherein R6 represents a substituent selected from the group consisting of CH3, CH2CH3, CH(CH3)2, CHxe2x95x90CH2, CHxe2x95x90CHCH3 and CHxe2x95x90C(CH3)2; wherein R3 and R4 can be a hydrogen atom or a methyl group; wherein xe2x80x9cnxe2x80x9d is an integer from 1 to 4 and wherein the mentioned B-ring and C-ring are aromatic; with Li/NH3 followed by the recovery of the compound of Formula 1 from the reaction mixture.
In accordance with the present invention, there is also provided a process for the preparation of a compound of Formula 1, wherein xe2x80x9czxe2x80x9d is a carbon atom, involving the reaction of a molecule of Formula 2-9 comprising A, B, C and D rings; 
wherein R1 represents a substituent selected from the group consisting of 1-pyrrolidinyl, 1-piperidinyl, methyl-1-pyrrolidinyl, dimethyl-1pyrrolidino, 4-morpholino, dimethylamino, diisopropylamino and 1-hexamethyleneimino; wherein R6 represents a substituent selected from the group consisting of CH3, CH2CH3, CH(CH3)2, CHxe2x95x90CH2, CHxe2x95x90CHCH3 and CHxe2x95x90C(CH3)2; wherein R3 and R4 can be a hydrogen atom or a methyl group; wherein xe2x80x9cnxe2x80x9d is an integer from 1 to 4 and wherein the mentioned B-ring and C-ring are aromatic; with catalytic amount of sulfuric acid, resulting in a dehydration reaction, followed by the recovery of the compound of Formula 1 from the reaction mixture.
In accordance with the present invention there is provided a pharmaceutical composition comprising the compound represented by FIG. 1 and at least one pharmaceutically acceptable carrier.
In accordance with the present invention there is provided a process for the preparation of a non-steroidal estrogen receptor antaganist, involving the reaction of a molecule of Formula 1-8, as previously defined, with either BBr3 or concentrated HBr followed by the recovery of the non-steroidal estrogen receptor antagonist from the reaction mixture.
In accordance with the present invention there is provided a process for the preparation of a non-steroidal estrogen receptor antaganist, involving the reaction of a molecule of Formula 2-7 with a with a reagent having the general formula Cl(CH2)nR1; both as previously defined, followed by the recovery of the non steroidal estrogen anataganist antagonist from the reaction mixture.
In accordance with the present invention there is provided a process for the preparation of a non-steroidal estrogen receptor antagonist, involving the reaction of a molecule of Formula 2-8, as previously defined, with a with a reducing agent selected from the group consisting of H2/Pd-C and NaBH4, followed by the recovery of the non-steroidal estrogen receptor anatagonist from the reaction mixture.
In accordance with the present invention there is provided a process for the preparation of a non-steroidal estrogen receptor antagonist, involving the reaction of a molecule of Formula 2-8, as previously defined, with with Li/NH3, followed by the recovery of the non-steroidal estrogen receptor anatagonist from the reaction mixture.
In accordance with the present invention there is provided a process for the preparation of a non-steroidal estrogen receptor antagonist, involving the reaction of a molecule of Formula 2-9, as previously defined, with a catalytic amount of sulfuric acid, resulting in a dehydration, followed by the recovery of the non-steroidal estrogen receptor anatagonist from the reaction mixture.
Unless defined otherwise, the scientific and technological terms and nomenclature used herein have the same meaning as commonly understood by a person of ordinary skill. Generally, procedures such as recovering a-or more compounds from a reaction mixture are common methods used in the art. Such standard techniques can be found in reference manuals such as for example Gordon and Ford (The Chemist""s Companion: A handbook of Practical Data, Techniques and References, John Wiley and Sons, New York, N.Y., 1972).
The present description refers to a number of routinely used chemical terms. Nevertheless, definitions of selected examples of such terms are provided for clarity and consistency.
As used herein, the terminology xe2x80x9cpharmaceutical compositionxe2x80x9d or xe2x80x9cpharmaceutical formulationxe2x80x9d , well known in the art, are used interchangeably.
As used herein, the terminology xe2x80x9crecoveringxe2x80x9d a desired compound or the like, well known in the art, refers to such a desired compound having been isolated from other components of a reaction mixture.
As used herein, the terminology xe2x80x9cconcentratedxe2x80x9d, well known in the art, refers to an acidic solution having a concentration equal to or higher than 10%.
The present invention comprises the genus of compounds represented by formula I useful in the treatment and or prevention of a variety of disorders or conditions such as breast cancer, uterine cancer, ovarian cancer, bone tissue loss (osteoporosis), cardiovascular diseases, premenstrual syndrome, uterine fibroma, endometriosis, precocious puberty, vasomotor symptoms associated with menopause, atrophic vaginitis, CNS disorders (including Alzheimer""s), infertility, glaucoma and elevated serum cholesterol.
It will be appreciated by those skilled in the art that reference herein to treatment extends to prophylaxis as well as the treatment of established diseases or symptoms. It will be further appreciated that the amount of a compound of the invention required for use in treatment will vary with the nature of the condition being treated, the age and condition of the patient and will be ultimately at the discretion of the attendant physician or medical practitioner. In general, however, doses employed for adult human treatment will typically be in the range of 0.001 mg/kg to about 100 mg/kg per day. The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example as two, three, four or more sub-doses per day.
The present invention also provides for novel pharmaceutical compositions of the compounds of Formula 1. While it is possible that compounds of the present invention may be therapeutically administered as the raw chemical, it is preferable to present the active ingredient as a pharmaceutical formulation. Accordingly, the present invention further provides for pharmaceutical formulations comprising a compound of Formula 1 or a pharmaceutically acceptable salt or ester thereof together with one or more pharmaceutically acceptable carriers and, optionally, other therapeutic and/or prophylactic ingredients. The carrier(s) must be xe2x80x9cacceptablexe2x80x9d in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
Formulations of the present invention may be administered in standard manner for the treatment of the indicated diseases, such as orally, parenterally, subligually, transdermally, rectally or via inhalation. For oral administration the composition may take the form of tablets or lozenges formulated in a conventional manner. For example, tablets and capsules for oral administration may contain conventional excipients such as binding agents, (for example, syrup, accacia, gelatin, sorbitol, tragacanth, mucilage of starch or polyvinylpyrrolidone), fillers (for example, lactose, sugar, microcrystalline cellulose, maize-starch, calcium phosphate or sorbitol), lubricants (for example, magnesium stearate, stearic acid, talc, polyethylene glycol or silica), disintegrants (for example, potato starch or sodium starch glycollate) or wetting agents, such as sodium lauryl sulphate. The tablets may be coated according to methods well-known in the art.
Alternatively, the compounds of the present invention may be incorporated into oral liquid preparations such as aqueous or oily suspensions, solutions, emulsions, syrups or elixirs. Moreover, formulations containing these compounds may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents such as sorbitol syrup, methyl cellulose, glucose/sugar syrup, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminum stearate gel or hydrogenated edible fats; emulsifying agents such as lecithin, sorbitan mono-oleate or acacia; non-aqueous vehicles (which may include edible oils) such as almond oil, fractionated coconut oil, oily esters, propylene glycol or ethyl alcohol; and preservatives such as methyl or propyl p-hydroxybenzoates or sorbic acid.
Such preparations may also be formulated as suppositories, e.g., containing conventional suppository bases such as cocoa butter or other glycerides. Compositions for inhalation can be typically provided in the form of a solution, suspension or emulsion that may be administered as a dry powder or in the form of an aerosol using a conventional propellant such as dichlorodifluoromethane or trichlorofluoromethane. Typical transdermal formulations comprise a conventional aqueous or non-aqueous vehicle, such as creams, ointments, lotions or pastes or are in the form of a medicated plaster, patch or membrane.
Additionally, compositions of the present invention may be formulated for parental administration by injection or continuous infusion. Formulations for injection may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle (e.g., sterile, pyrogen-free water) before use.
Compositions of the present invention may be formulated for nasal administration. Such formulations may comprise the compound of the present invention and a non-toxic pharmaceutically acceptable nasal carrier. Suitable non-toxic pharmaceutically acceptable nasal carriers for use in the compositions of the present invention will be apparent to those skilled in the art of nasal pharmaceutical formulations. Obviously the choice of suitable carriers will depend on the exact nature of the particular nasal dosage form desired, as well as on the identity of the active ingredient(s). For example, whether the active ingredient(s) are to be formulated into a nasal solution (for use as drops or spray), a nasal suspension, a nasal ointment or a nasal gel. Preferred nasal dosage forms are solutions, suspensions and gels, which contain a major amount of water (preferably purified water) in addition to the active ingredient(s). Minor amounts of other ingredients such as pH adjusters (e.g., a base such as NaOH), emulsifiers or dispersing agents (e.g. polyoxyethylene 20 sorbitan mono-oleate), buffering agents, preservatives, wetting agents and jelling agents (e.g. methylcellulose) may also be present. Also, a sustained release composition (e.g. a sustained release gel) can be readily prepared.
The composition according to the invention may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example, subcutaneously or intramuscularly) or by intramuscular injection. Accordingly, the compounds of the invention may be formulated with suitable polymeric or hydrophobic materials (such as emulsion in an acceptable oil), ion exchange resins or as sparingly soluble derivatives or sparingly soluble salts.